Drug discovery processes are very lengthy. A conventional process involves testing and screening of thousands of individual compounds for a desired therapeutical activity. Historically, less than 1 in 10,000 of the synthetic compounds have made it to the drug market, at costs greater than $200 million per drug (Ganellin, C. R., 1992, in Medicinal Chemistry for the 21st Century, Ed. by Wermuth, C. G.; Koga, N.; Konig, H.; and Metcalf, B. W. Blackwell Scientific Publications, London; pp. 3-12).
Drugs have been sought from natural products for many years. Complex mixtures made from cells or their secondary metabolites have been screened for biological activity. When a desired biological activity has been found in such a complex mixture, the particular chemical which has the activity has been purified, using the biological activity as the means of identifying the component of the mixture which contains the desired activity.
An alternative method for screening compounds for desirable biological activities has been to screen individual compounds which have been synthesized and saved in libraries of drug or chemical companies or research institutes. The compounds in these libraries were often chosen for synthesis and screening because they had a particular functionality thought to be relevant to a particular biological activity.
More recently, some companies have begun to create their own peptide and oligonucleotide libraries to screen for a particular biological function. "Peptide Library Synthesis and Screening Strategies for Drug Development", Genetic Engineering News, May 1, 1993, page 6; "Ixsys Licenses In Vitro Monoclonal Process", Genetic Technology News, vol. 12, page 14, October 1992; and Ladner, U.S. Pat. No. 5,223,409; "In Vitro Evolution Creates Novel Drugs," Genetic Engineering News, page 1, Apr. 15, 1993. The combinatorial peptide and nucleotide libraries described to date involve the sequence randomization of individual monomers using a single naturally existing biological linkage (such as 3'-5' phosphate linkage of nucleotides or amide linkage of peptides).
J. H. Musser, "Trends in New Lead Identification" in Medicinal Chemistry for the 21st Century, edited by Wermuth, Koga, Konig and Metcalf, teaches that carbohydrates have the potential for greater complexity than polypeptides or oligonucleotides. He opines that "of all the structural types, carbohydrates have the greatest theoretical potential for specificity and new lead generation."
Carbohydrates are a large family of organic molecules with highly functionalized carbon skeletons. They share the structure C.sub.x (H.sub.2 O).sub.y. In fact, this may be the only readily available family of molecules where almost every carbon within the skeleton is functionalized. These functionalizations and related stereochemical differences also result in different chemical reactivities for individual carbon atoms.
The great potential of carbohydrates for use in generating organic compound libraries rests within the inherent character of this class of compounds. Almost every carbon in a given carbohydrate has a hydroxyl functionality (or other oxygen-containing functional group) attached to it. Different spatial arrangements (stereochemical arrangements) of these hydroxyl groups result in different carbohydrates; for example, the difference between glucose and galactose is attributable to the stereochemistry of the hydroxyl group attached to the C-4 carbon. Different linkages between carbohydrates derived from these hydroxyl functionalities (i.e., by removal of a water molecule) also result in different carbohydrates. As a consequence, the potential number of different saccharides generated by combining several saccharities together can be very large.
When two hexoses are linked together via a glycosidic bond (a chemical linkage involving the anomeric carbon of at least one of the saccharides), eleven different disaccharides can theoretically be obtained. A mixture of three monosaccharides can, in theory, generate as many as 1056 possible trisaccharide combinations, and a mixture of five different monosaccharides can be assembled into 31 million pentasaccharides. In addition, if the reaction conditions produce sugar anhydride linkages, the combinatory possibilities increase many fold. For instance, two identical monosaccharides can generate a total number of 26 different dimers of sugar anhydrides and glycosides.
Recently, new screening processes have been developed which have the potential for high throughput, i.e., many compounds per unit time can be tested individually for a particular biological activity. See "Progenics Improves the Screening Process", Genetic Technology News, vol. 9, page 5, May 1989; "Nova gets $2.5 Million for AIDS", Biotechnology Newswatch, vol. 8, page 2, Dec. 19, 1988; "RT speeds screening for new drugs" Chemical Week, Apr. 15, 1987, page 19. Such screening techniques involve testing for inhibitors of specific proteins, or binding to particular cellular receptors. These screening processes are typically performed on pre-existing libraries of chemicals. See "Newsfront: Companies" Chemical Engineering, page 35, Sep. 16, 1985; and "RT speeds screening for new drugs" Chemical Week, Apr. 15, 1987, page 19.
The potential diversity of polyhydroxyl-containing organic compounds and the newly developed screening procedures, have together generated an opportunity for devising new methods to generate rapidly novel, large libraries of diverse chemicals for screening for bioactive compounds.